Synthesis, characterization and crystal structure of pentyl 2-(1H-indole-2-carboxamido)benzoate

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Pentyl 2-(1H-indole-2-carboxamido)benzoate (5) is obtained in good yield as stable crystals by reaction of pentyl 2-amino benzoate (6) with indole-2-carbonyl chloride acid (7) in the presence of pyridine. The crystal structure of 5 confirms the presence of intramolecular hydrogen bonding (N-H…O) which produces a six-membered ring, and the molecules are linked together by intermolecular hydrogen forces (N-H…O).

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Nội dung Text: Synthesis, characterization and crystal structure of pentyl 2-(1H-indole-2-carboxamido)benzoate

Current Chemistry Letters 8 (2019) 63–68 Contents lists available at GrowingScience Current Chemistry Letters homepage: www.GrowingScience.com Synthesis, characterization and crystal structure of pentyl 2-(1H-indole-2- carboxamido)benzoate Kamal Sweidana, Monther Khanfara, Ala'a Al-Shamaileha, Mahmoud Sunjukb and Rajendra Joshic* a Department of Chemistry, The University of Jordan, Amman 11942, Jordan b Department of Chemistry, Hashemite University, Zarqa 13115, Jordan c Department of Chemical Science and Engineering, School of Engineering, Kathmandu University, Nepal CHRONICLE ABSTRACT Article history: Pentyl 2-(1H-indole-2-carboxamido)benzoate (5) is obtained in good yield as stable crystals Received November 21, 2018 by reaction of pentyl 2-amino benzoate (6) with indole-2-carbonyl chloride acid (7) in the Received in revised form presence of pyridine. The crystal structure of 5 confirms the presence of intramolecular November 21, 2018 hydrogen bonding (N-H…O) which produces a six-membered ring, and the molecules are Accepted December 28, 2018 linked together by intermolecular hydrogen forces (N-H…O). Available online December 28, 2018 Keywords: Carboxamide Indole Nucleophilic acyl substitution NMR/MS data © 2019 by the authors; licensee Growing Science, Canada. X-ray structure determination 1. Introduction Heterocyclic moieties are present in a wide variety of drugs, due to their remarkable medicinal properties. Various derivatives of indole-2-carboxamide were synthesized and shown to exhibit different biological activities; examples include compounds 1 (acting against Mycobacterium tuberculosis (Mtb)), 2 (an antihyperlipedimic agent), 3 (a PI3Kα/EGFR inhibitor) and 4 (an anticancer agent) (Fig. 1).1-4 Amide bond formation utilizes either the reaction of carboxylic acid derivatives with amines in the presence of bases, such as triethylamine or pyridine. These reactions are called indirect amidation.5 Alternatively, direct amidation utilizes reactions of free carboxylic acid with amines through thermal direct reaction or by using a metal-catalyst.6 In continuation of our further search for new derivatives of heterocyclic moieties,2-4,7 we report herein the synthesis and full characterization of compound 5 (Fig. 1). 2. Results and Discussion Compound 5 was prepared by reacting 6 with 7 in dry chloroform and in the presence of dry pyridine which was employed as base and catalyst, as shown in Scheme 1. Fischer esterification of 2- aminobenzoic acid with 1-pentanol, in the presence of sulfuric acid, afforded compound 6. It is worthy * Corresponding author. Tel: ++977-11-415100 E-mail address: rajendra.joshi@ku.edu.np (R. Joshi) © 2019 by the authors; licensee Growing Science, Canada doi: 10.5267/j.ccl.2018.012.005
64 to mention that the reaction of isatoic anhydride with 1-pentanol produced 6.8 On the other hand, compound 7 was used rather than the indole-2-carboxylic acid itself, since it is more reactive towards nucleophilic acyl substitution reaction, in particular, if the nucleophile (such as aromatic amine) is weak. Pyridine was employed in this type of reaction to trap the evolved hydrogen chloride gas by forming pyridinium chloride salt, which also helps in the conversion of 7 into more reactive species (pyridium adduct) towards nucleophilic acyl substitution reaction. This approach of synthesis has many advantages such as good yield is usually obtained and milder experimental conditions can be used. In contrast to other methodologies that used ester derivatives instead of acyl halides as reactant, strong base (e. g. sodium alkoxide) in refluxing DMF for long time is usually preferred and the yield is even low. On the other hand, coupling agent should be employed when carboxylic acid itself is acting as a starting material to form the amide group. Fig. 1. Chemical structures of some indole-containing molecules O O C COOH 1-pentanol NH2 NH2 H+ , heat 6 H H N OH SOCl2 N Cl THF, heat O O 7 dry pyridine 6 + 7 5 dry CHCl3 Scheme 1. Synthesis of the target product 5 In 1H NMR spectrum of 5, signals of aliphatic protons have been observed in the range 0.8 - 5 ppm, while the signals of two protons in both N-H groups were highly deshielded (11-12 ppm) in deuterated DMSO solvent due to intra-hydrogen bonding with solvent molecules. On the other hand, the carbon atom of the amide group resonates, as expected, at 160.1 ppm in 13C-NMR spectrum; other peaks are observed in the expected ranges. The results of DEPT experiments are in conformity with the proposed
K. Sweidan et al. / Current Chemistry Letters 8 (2019) 65 structure, four methylene groups (CH2) show down peaks at four different positions. Further, the mass spectrum of compound 5 displays the correct molecular ion peaks for which the measured HRMS data are in good agreement with the calculated values. Elemental analysis data assures the purity of the product. 2.1 Description of the Crystal Structure Single X-ray crystallography measurements show that 5 crystallizes in the monoclinic system, with space group P21/m and crystallographic data are listed in Table 1. The asymmetric unit of 5 (Fig. 2) contains one molecular unit. Crystal structure of 5 reveals the presence of intramolecular N-H…O bond [O(2)…H(2) 1.918, N(2)…H(2) 0.859 Å, N(2)-H(2)…O(2) 139.2°]. As expected, the bond length of C(10A)-O(1), in the amide group, is slightly longer than that of C(11A)-O(2), in the ester group, (1.220 compared to 1.204 Å); this is due to the resonance effect in the amide group. Intramolecular hydrogen bonding forms six-membered ring, in which the amide NH group is considered as proton donor and the oxygen atom of the carbonyl of the ester group as proton acceptor. The indolic NH proton is involved in intermolecular hydrogen bonding to the oxygen atom (of the amide group) of an adjacent molecule leading to a polymeric chain structure (Fig. 3) [O(1)…H(1) 2.060, N(1)…H(1) 0.860 Å, N(1)-H(1)…O(1) 161.5°]. The molecule is almost planar and the dihedral angle is 1.98 °. Table 1. Crystal data and structure refinement parameters for 5 Crystal system Monoclinic Empirical formula C21H22N2O3 -1 Formula weight (g mol ) 350.42 Temperature/K 293(2) Space group P21/c a/Å 9.9711(8) b/Å 7.8134(9) c/Å 23.645(2) β/° 99.208(7) 3 V/Å 1818.4(3) Z 4 Density g/cm3 1.2799 -1 MoKα /mm 0.086 F(000) 744.4 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/° 5.82 to 58.54 Index ranges –12 ≤ h ≤ 13, –9 ≤ k ≤ 10, –31 ≤ l ≤ 18 Reflections collected 8789 Independent reflections 4210 [Rint = 0.0329, Rsigma = 0.0518] Data/restraints/parameters 4210/0/236 2 Goodness-of-fit on F 1.059 Final R indexes [I>=2σ (I)] R1 = 0.0945, wR2 = 0.2290 Final R indexes [all data] R1 = 0.1344, wR2 = 0.2507 -3 Largest diff. peak/hole / e Å 0.47/–0.45
66 Fig. 2. Thermal ellipsoid drawing (35% probability level) of the asymmetric unit of 5. Fig. 3. View of the dimers of 5 in the crystal 3. Conclusions The target compound 5 has been successfully prepared in reaction which follows the mechanism of nucleophilic acyl substitution of acyl chloride (7) and aromatic primary amine (6). Hydrogen-bond donor (N-H) and hydrogen-bond acceptor (C=O) functional groups were incorporated into its structure. The structure of the target product was fully characterized. Further, X-ray structural analyses of 5 shows that there are intra and inter hydrogen bonding forces. Acknowledgments The authors would like to thank Kathmandu University for supporting this research. Also, the authors gratefully acknowledge the financial support from the University of Jordan, Deanship of Scientific Research. 4. Experimental The following chemicals were purchased and used without further purification: indole-2-carboxylic acid (Aldrich, 98%), 2-aminobenzoic acid (Aldrich, 98%), oxalyl chloride (Aldrich, 98%), N,N- dimethylformamide (DMF) (HPLC grade Tedia), pyridine (Tedia), ethyl acetate (AZ chem), 1-pentanol
K. Sweidan et al. / Current Chemistry Letters 8 (2019) 67 (HPLC grade Acros). Compound 7 was prepared according to the published procedure.3 Chloroform (Labchem) was purified by stirring under anhydrous sodium sulfate overnight then distilled. NMR analysis was done using Bruker-Avance III 500 MHz spectrometers with TMS as the internal standard. Coupling constant (J) values are given in Hertz (Hz). High resolution mass spectra (HRMS) were measured (in positive ion mode) using electrospray ion trap (ESI) technique by collision-induced dissociation on a BrukerAPEX-4 (7 Tesla) instrument. The FT-IR measurements (500-4000 cm-1) were recorded using ThermoNicolet 670 FT-IR spectrophotometer. Thin Layer Chromatography (TLC) was performed using Merck aluminum plates pre-coated with silica gel PF254; (20 x 20) cm x 0.25 mm, and detected by visualization of the plate under UV lamp (ƛ = 254 nm). Melting point was measured with an SMP 10 Stuart apparatus. Elemental analysis was obtained using Euro Vector Elemental analyzer model EUROEA3000 A, (Redavalle), Italy. Single-crystal X-ray diffraction data were collected using an Oxford Diffraction XCalibur, equipped with (Mo) X-ray Source (λ = 0.71073 Å) at 293(2) K. Pentyl 2-aminobenzoate (6). To a mixture of 2-aminobenzoic acid (0.5 g, 3.6 mmol) and 1-pentanol (6.5 mL, 60 mmol), sulfuric acid (0.8 mL, 14.7 mmol) was added dropwise at 0 °C; the resulting solution was stirred for 30 minutes at room temperature, then refluxed for 24 h. After cooling, the resulting solution was neutralized with 1 M NaHCO3 (30 mL), and then the organic layer was extracted with ethyl acetate (20 mL). The organic solvent was evaporated under reduced pressure to get the desired product. Yield: 0.54 g (73%). 1H NMR spectrum (CDCl3), δ, ppm: 0.86 (t, J = 7.2, Hz, 3H, CH3), 1.30-1.38 (m, 4 H, 2CH2), 1.73 (m, 2H, CH2), 4.34 (t, J = 6.5 Hz, 2H, CH2), 5.01 (s, 2H, NH2), 6.34 (d, J = 7.9 Hz, 1H, H6), 6.91 (m, 1H, H4); 7.04 (m, 1H, H5), 7.91 (d, J = 8.3 Hz, 1H, H3). 13C NMR spectrum (CDCl3), δC, ppm: 14.0 (CH3), 21.9 (CH2), 27.8 (CH2), 27.9 (CH2), 65.6 (CH2), 127.5 (C2), 131.2 (C3), 124.7 (C4), 134.9 (C5), 120.7 (C6), 140.7 (C1), 168.1 (C=O ester). Found, %: С 69.69; Н 8.41; N 6.45. С12Н17NО2. Calculated, %: С 69.54; Н 8.27; N 6.76. M 207. Pentyl 2-(1H-indole-2-carboxamido)benzoate (5). An exact amount of 6 (2.0 g, 9.7 mmol) in CHCl3 (10 mL) was added dropwise to a solution of 7 (0.9 g, 5.0 mmol) in CHCl3 (20 mL) and pyridine (5 mL) at -5 °C. The resulting solution was stirred overnight to afford the desired product as white precipitate which was filtrated off and dried under vacuum. Yield: 1.1 g (63 %), mp 183-184°C, hexane: ethyl acetate (8:2) Rf 0.75. 1H NMR spectrum (DMSO-d6), δ, ppm: 0.84 (t, J = 7.2, Hz, 3H, CH3), 1.28- 1.38 (m, 4 H, CH2), 1.76 (m, 2H, CH2), 4.39 (t, J = 6.5, 6.50 Hz, 2H, CH2), 7.12 (t, J = 7.4, 7.3 Hz, 1H, H6), 7.27-7.24 (m, 2H, H7, H4`), 7.19 (s, 1H, H3), 7.41 (d, J = 8.2 Hz, 1H, H5), 7.68-7.77 (m, 2H, H8, H5`), 8.09 (d, J = 7.9 Hz, 1H, H3`), 8.49 (d, J = 8.3 Hz, 1H, H6`), 11.67 (s, 1H, NH-amide), 11.92 (s, 1H, N1).13C NMR spectrum (DMSO-d6), δC, ppm: 14.0 (C16A), 21.9 (C15A), 27.8 (C14A), 27.9 (C13A), 65.6 (C12A), 103.5 (C8), 117.2 (C3), 127.5 (C2B), 131.2 (C3B), 124.7 (C4B), 134.9 (C5B), 120.7 (C6B), 140.7 (C1B), 121.0 (C6), 122.4 (C5), 122.4 (C7), 131.8 (C4), 137.7 (C9), 137.7 (C2), 159.8 (C10A), 168.2 (C11A). IR spectrum, v, cm-1: 3284 (N-H amide), 3284 (N-H indole), 1681 (C=O). HRMS ((-)-ESI): m/z = 349.15577 (calcd. 349.15537 for C20H21N2O3, [M-H]). Found, %: С 71.71; Н 6.42; N 7.65. С20Н22N2О3. Calculated, %: С 71.98; Н 6.33; N 7.99. M 350. Crystallographic Data Crystals of 5 were obtained by slow evaporation of a CH2Cl2 solution of 5. Data collection, reduction, and cell refinement were performed using the software package CrysAlisPro.9 Analytical absorption corrections were applied using spherical harmonics implemented in SCALE3 (ABSPACK) scaling algorithm. Crystal structure was solved by direct methods, using the program OLEX2, followed by Fourier synthesis, and refined on F2 with SHELXL-97.10 Anisotropic least-squares refinement of non- H atoms was applied. All crystallographic plots were obtained using the Diamond program.11 A summary of the crystallographic data and structure refinement parameters is given in Table 1.
68 Data Availability Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB21EZ, UK. Copies of the data can be obtained free of charge on quoting the depository number CCDC-1867234 (Fax: +44-1223-336-033; E-Mail: deposit@ccdc.cam.ac.uk, http:// www.ccdc.cam.ac.uk). Conflicts of Interest The authors declare that there is no conflict of interest regarding the publication of this paper. References 1 Kondreddi, R. R., Jiricek, J., Rao, S. P. S., Lakshminarayana, S. B., Camacho, L. R., Rao, R., Herve, M., Bifani, P., Ma, N. L., Kuhen, K., Goh, A., Chatterjee, A. K., Dick, T., Diagana, T. T., Manjunatha, U. H., and Smith, P. W. (2013) Design, synthesis, and biological evaluation of indole-2- carboxamides: A promising class of antituberculosis agents. J. Med. Chem., 56 (21) 8849-8859. 2 Shattat, G., Al-Qirim, T., Abu Sheikha, G., Al-Hiari, Y., Sweidan, K., Al-Qirim, R., Hikmat, S., Hamadneh, L., and Al-Kouz, S. (2013) The Pharmacological effects of novel 5-fluoro-N-(9,10- dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamide derivatives on plasma lipid profile of Triton-WR-1339-induced Wistar rats J. Enzyme Inhib. Med. Chem., 28 (4) 863-869. 3 Sweidan, K., Sabbah, D., Bardaweel, S., Abu Dush, K., Abu Sheikha, G., and Mubarak, M. S. (2016) Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors Bioorg. Med. Chem. Lett., 26 (11) 2685-2690. 4 Sweidan, K., Sabbah, D., Bardaweel, S., Abu Sheikha, G., Al-Qirim, T., and Salih, H. (2017) Facile synthesis, characterization, and cytotoxicity study of new 3-(indol-2-yl)bicyclotetrazatridecahexaens Can. J. Chem., 95 (8) 858-862. 5 Shivaraj, Y., Naveen, M. H., Vijayakumar, G. R., and Kumar, D. B. A. (2013) Design, synthesis and antibacterial activity studies of novel quinoline carboxamide derivatives J. Korean Chem. Soc., 57 (2) 241-245. 6 Lanigan, R. M., and Sheppard, T. D. (2013) Recent developments in amide synthesis: Direct amidation of carboxylic acids and transamidation reactions Eur. J. Org. Chem., 2013 (33) 7453-7465. 7 Mallah, E., Sweidan, K., Engelmann, J., Steimann, M., Kuhn, N., and Maier, M. E. (2012) Nucleophilic substitution approach towards 1,3-dimethylbarbituric acid derivatives—new synthetic routes and crystal structures Tetrahedron, 68 (4) 1005-1010. 8 Rao, D. V., Ramana, V. V. R., and Raghunanda, P. (1985) Studies on embelin. Part III. Synthesis and biological activity of some anthranilic acid ester derivatives of embelin and embelin di-O-methyl ether. Indian J. Chem. B, 24B (9) 988-991. 9 CrysalisPro Software System (version 1.171.35.11; release 16-05-2011), Intelligent Data Collection and Processing Software for Small Molecule and Protein Crystallography, Agilent Technologies Ltd., Yarnton, Oxfordshire (U.K.), (2011). 10 G. M. Sheldrick, Shelxtl (version 6.10), Bruker Analytical X-ray Instruments Inc., Madison, WI (USA), 2000.Sheldrick, GM., (SHELXL-97, Program for X-ray Crystal Structure Refinement) (Göttingen, Germany: University of Göttingen, 1997). 11 Images generated using Diamond (R): A crystal and molecular structures program for Windows. Crystal Impact GbR, Bonn, Germany, version 3.1a (2005). Author: Klaus Brandenburg. © 2018 by the authors; licensee Growing Science, Canada. This is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).